Co-factor-independent Phosphoglycerate Mutase of Leishmania Donovani Modulates Macrophage Signalling and Promotes T-cell Repertoires Bearing Epitopes for Both MHC-I and MHC-II

Parasitology. 2018 Mar;145(3):292-306. doi: 10.1017/S0031182017001494. Epub 2017 Nov 15.

Abstract

Immunoactivation depends upon the antigen potential to modulate T-cell repertoires. The present study has enumerated the effect of 61 kDa recombinant Leishmania donovani co-factor-independent phosphoglycerate mutase (rLd-iPGAM) on mononuclear cells of healthy and treated visceral leishmaniasis subjects as well as on THP-1 cell line. rLd-iPGAM stimulation induced higher expression of interleukin-1β (IL-1β) in the phagocytic cell, its receptor and CD69 on T-cell subsets. These cellular activations resulted in upregulation of host-protective cytokines IL-2, IL-12, IL-17, tumour necrosis factor-α and interferon-γ, and downregulation of IL-4, IL-10 and tumour growth factor-β. This immune polarization was also evidenced by upregulation of nuclear factor-κ light-chain enhancer of activated B cells p50 and regulated expression of suppressor of mother against decapentaplegic protein-4. rLd-iPGAM stimulation also promoted lymphocyte proliferation and boosted the leishmaniacidal activity of macrophages by upregulating reactive oxygen species. It also induced 1·8-fold higher release of nitric oxide (NO) by promoting the transcription of inducible nitric oxide synthase gene. Besides, in silico analysis suggested the presence of major histocompatibility complex class I and II restricted epitopes, which can proficiently trigger CD8+ and CD4+ cells, respectively. This study reports rLd-iPGAM as an effective immunoprophylactic agent, which can be used in future vaccine design.

Keywords: Leishmania donovani; adaptive immunity; co-factor-independent phosphoglycerate mutase; innate immunity; visceral leishmaniasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Coenzymes / deficiency
  • Coenzymes / genetics
  • Computer Simulation
  • Cytokines / drug effects
  • Cytokines / immunology
  • Epitopes, T-Lymphocyte / drug effects
  • Epitopes, T-Lymphocyte / immunology*
  • Genes, MHC Class I / immunology
  • Genes, MHC Class II / immunology
  • Humans
  • Interleukin-1beta / drug effects
  • Interleukin-1beta / immunology
  • Leishmania donovani / enzymology*
  • Leishmania donovani / immunology*
  • Leishmaniasis, Visceral / immunology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / parasitology
  • Lymphocyte Activation / drug effects
  • Macrophages / immunology*
  • Macrophages / parasitology
  • NF-kappa B p50 Subunit / drug effects
  • NF-kappa B p50 Subunit / genetics
  • Nitric Oxide
  • Nitric Oxide Synthase Type II / drug effects
  • Phosphoglycerate Mutase / genetics
  • Phosphoglycerate Mutase / immunology*
  • Phosphoglycerate Mutase / pharmacology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology*
  • Th1 Cells

Substances

  • Coenzymes
  • Cytokines
  • Epitopes, T-Lymphocyte
  • Interleukin-1beta
  • NF-kappa B p50 Subunit
  • Recombinant Proteins
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Phosphoglycerate Mutase